1. Field of the Invention
The present invention relates generally to cell surface receptors, and more specifically, to Corticotropin-Releasing Factor2 receptors.
2. Description of the Related Art
Corticotropin-releasing factor (“CRF”) is a 41-amino acid peptide originally isolated from the hypothalamus by virtue of its ability to stimulate the production of adrenocorticotropic hormone (“ACTH”) and other proopiomelanocortin (“POMC”) products of the anterior pituitary (Vale et al., Science 213:1394–1397, 1981). Briefly, CRF is believed to initiate its biological effects by binding to a plasma membrane receptor which is distributed throughout the brain (DeSouza et al., Science 224:1449–1451, 1984), pituitary (Wynn et al., Biochem. Biophys. Res. Comm. 110:602–608, 1983), adrenals (Udelsman et al., Nature 319:147–150, 1986) and spleen (Webster, E. L., and E. B. DeSouza, Endocrinology 122:609–617,1988). This receptor is coupled to a GTP-binding protein (Perrin et al., Endocrinology 118:1171–1179, 1986) which mediates CRF-stimulated increase in intracellular cAMP (Bilezikjian, L. M., and W. W. Vale, Endocrinology 113:657–662,1983).
In addition to its role in stimulating the production of ACTH and POMC, CRF is also believed to coordinate many of the endocrine, autonomic, and behavioral responses to stress, and may be involved in the pathophysiology of affective disorders. Moreover, CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al., J. Clin. Invest. 90:2555–2564,1992; Sapolsky et al., Science 238:522–524, 1987; Tilders et al., Regul. Peptides 5:77–84, 1982; Fisher et al., Reg. Peptide 5:153–161,1983).
A receptor for CRF has been cloned from rat (Perrin et al., Endo 133(6):3058–3061,1993), and human brain (Chen et al., PNAS 90(19):8967–8971, 1993; Vita et al., FEBS 335(1):1–5, 1993). This receptor is a 415 amino acid protein comprising seven membrane spanning domains, and has a predicted molecular weight of 44,000 daltons. A comparison of identity between rat and human sequences shows a high degree of homology (97%) at the amino acid level. In addition, Scatchard analysis of recombinantly produced human receptor demonstrates a single component site, with a high affinity (Kd of 1.6±0.3 nM) for CRF.
The present invention provides new, previously unidentified CRF receptors, designated as the “Corticotropin-Releasing Factor-2” (“CRF2”), Corticotropin-Releasing Factor receptors. In addition, the present invention provides compositions and methods which utilize such CRF2 receptors, as well as other, related advantages.